Vaccine strategy has been proven effective in providing protection against a host of maladies. Yet there are many pathogens and infections for which this strategy is not effective. Presently, there is an increasing need for more effective vaccines to combat acute and chronic infections and diseases. While traditional vaccine strategy employs live, attenuated pathogens as immunogens, contemporary vaccine development employs recombinant or synthetic subunit vaccines which usually offer improved safety and more precise targeting. However, subunit vaccines are characterized by poor immunogenicity and often must be co-administered with an adjuvant to enhance the immune response.
A vaccine adjuvant is a substance that is able to enhance the immune responses to the accompanying antigen of the vaccine formulation. While numerous classes of compounds have been explored as vaccine adjuvants, Alum, a mixture of aluminum salts, is still the most popular adjuvant for human vaccine use. In fact Alum was the only approved adjuvant for human vaccines for more than 70 years. It was not until late 2009 that the FDA approved GlaxoSmithKline's AS04 adjuvant (a proprietary combination of Alum and monophosphoryl lipid A, MPL®) (Garcon et al., Expert Rev. Vaccines, 6: 723-739, 2007) which was used for the Cervarix vaccine to immunize against human papillomavirus (HPV). There however remains a great need to develop and characterize new adjuvants for vaccine therapies. Discovery of novel adjuvants has emerged as a critical frontline effort in the development of modern vaccine formulations.
Lipopolysaccharide (LPS), also known as endotoxin, is the outer membrane component of Gram-negative bacteria. LPS was long ago described as a potent stimulus of antibody responses, and extensive studies led to the conclusion that the adjuvant activity of LPS was systemic (Johnson, A. G., “Adjuvant action of bacterial endotoxins on the primary antibody response”, in Landy, M. and Braun, W. (eds.), Bacterial Endotoxins, Rutgers University Press, New Brunswick, Conn., pp. 252-262, 1964), rather than local, unlike aluminum or oil-based adjuvants which only worked if co-administered with the antigen. The active component of LPS for its immunostimulatory activity was later determined to be the lipophilic anchor of the molecule, known as lipid A. Both LPS and lipid A are too toxic to be used as an adjuvant for human vaccines. As such, much research has been conducted to separate the adjuvant activity from the pyrogenicity and toxicity of the parent LPS and lipid A molecules. As a result of many years' study and development, MPL® was approved by the FDA for human vaccine use in the Cervarix HPV vaccine developed by GlaxoSmithKline. MPL® is a product purified from cultured bacteria, which contains a mixture of structurally modified lipid A molecules. Through structural modification, the toxicity of lipid A has been reduced while the immunostimulatory activity of these molecules largely remains.
The molecular target and mechanisms of action for LPS/lipid A in regard to their immunostimulatory activity have been identified, thanks to the discovery of a group of proteins known as Toll-like receptors (TLRs) about 20 years ago. TLRs play important roles in innate immunity and the development of adaptive immune response. LPS/lipid A is recognized by Toll-like receptor 4 (TLR4), a member of TLR protein family, which is associated with another protein MD-2. The activation of the TLR4/MD-2 receptor complex leads to downstream signalling pathways that ultimately regulate innate immunity as well as the development of adaptive immune response. The crystal structure of TLR4/MD-2 with the bound ligand LPS has recently been determined (Park et al., Nature, 458: 1191-1196, 2009), which provides direct evidence for the molecular basis of recognition of LPS/lipid A by TLR4/MD-2. The recently approved adjuvant MPL® has also been shown to exert its activity through the mediation of TLR4/MD-2. It is now well recognized that TLR4 agonists are an important class of immunostimulatory vaccine adjuvants.
In the present disclosure, we report a group of novel lipid A mimics. These compounds are potentially useful as immune stimulants and/or modulators to treat various diseases.